Effects of alteplase for acute stroke according to criteria defining the eu and us marketing authorizations: individual-patient-data meta-analysis of randomized trials
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- Figure legends Figure 1: Effect of rt−PA on an excellent stroke outcome (mRS0−1) in groups defined by the current EU label as well as an EU label without an upper age restriction
- Figure 2: Effect of rt-PA on 90-day mortality in groups defined by the current and extended labels in the EU and US
- Figure 3: Effect of rt−PA on an excellent stroke outcome (mRS0−1) in groups defined by the current US label as well as a US label with a 4.5h time window
- Figure 4: Distribution of mRS at 3−6 months by randomized treatment allocation in groups defined by the current and extended labels in the EU and US
- Table 1: Contraindications to alteplase treatment for stroke in FDA and EMA approved product inserts and AHA and ESO guidelines
- Blood pressure at treatment
- Prior stroke and diabetes
- Aneurysms, neoplasm, arterial/venous malformation
- Extensive ischemic change or mass effect
- EU label US label Total
Summary Hypothetical revisions of the treatment labels for alteplase after acute ischemic stroke, increasing the time window to 4.5 hours for the US criteria and removing the upper age limit from the EU criteria, substantially increased the proportion of patients for whom treatment was of net benefit without elevating 90-day mortality. These revisions are in reasonable alignment with existing ESO recommendations on alteplase use. The available evidence indicates that the current US and EU marketing authorizations for the use of intravenous alteplase following acute ischemic stroke are unduly restrictive, and may well be contributing to unnecessary disability. Appendix Included Trials ATLANTIS A and B (Gregory Albers, James Grotta, Maarten Lansberg, Jean Marc Olivot); ECASS-1, ECASS-2, ECASS-3 (Erich Bluhmki, Werner Hacke, Markku Kaste, Kennedy R Lees, Ruediger von Kummer, Danilo Toni, Nils Wahlgren); EPITHET (Stephen Davis, Geoffrey Donnan, Mark Parsons); IST-3 (Peter Sandercock, Joanna Wardlaw, Richard Lindley, Gordon Murray, Geoff Cohen, William Whiteley); NINDS A and B (Thomas Brott, James Grotta, Patrick Lyden, John Marler, Barbara Tilley). STT Statistical Analysis Centre and Secretariat: Colin Baigent, Lisa Blackwell, Erich Bluhmki, Kelly Davies, Jonathan Emberson, Heather Halls, Lisa Holland, George Howard, Clare Mathews, Samantha Smith, Kate Wilson. STT collaborative group: Gregory Albers, Craig Anderson, Colin Baigent, Lisa Blackwell, Erich Bluhmki, Thomas Brott, Geoffrey Cohen, Stephen Davis, Geoffrey Donnan, Jonathan Emberson, James Grotta, Werner Hacke, Michael Hill, George Howard, Markku Kaste, Masatoshi Koga, Ruediger von Kummer, Maarten Lansberg, Kennedy R Lees, Richard I Lindley, Patrick Lyden, Gordon Murray, Jean Marc Olivot, Mark Parsons, Tom Robinson, Peter Sandercock, Barbara Tilley, Danilo Toni, Kazunori Toyoda, Nils Wahlgren, Joanna Wardlaw, William Whiteley, Gregory J del Zoppo Sources of Funding This collaboration is coordinated by the Clinical Trial Service Unit & Epidemiological Studies Unit at the University of Oxford, UK. The Unit receives core funding from the UK Medical Research Council and the British Heart Foundation. This work also received support from the University of Glasgow and University of Edinburgh. Conflicts of interest KRL reports fees and expenses from American Stroke Association, Applied Clinical Intelligence, Atrium, Boehringer Ingelheim, EVER NeuroPharma, Hilicon, Nestlé, Novartis, Servier and Stroke Academic Industry Roundtable; and research funding to the University of Glasgow and to the Virtual International Stroke Trials Archive from Genentech, and is past president of the European Stroke Organisation. CB, LB, and JE are involved in research funded by Merck to the University of Oxford as sponsor but report no personal conflicts. EB is employed by Boehringer Ingelheim. SD has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Medtronic and Pfizer. GD is co-principal investigator for the EXTEND trial using alteplase and has received honoraria from Boehringer Ingelheim, Bayer, Pfizer, Sanofi and Merk Sharp & Dohme. JG has acted as a consultant for Frazer Ltd and Stryker, has received grant support from the American Heart Association, Genentech and Behring, and has received grant support within the past 3 years from Haemonetics and Medtronic. MKa reports fees and expenses from Lundbeck A/S, Mitsubishi Pharma Europe, Siemens AG. RvK reports fees from H. Lundbeck A/S, Boehringer Ingelheim, Covidien, Brainsgate, Synarc, and Penumbra, Inc. RIL has received honoraria from Boehringer Ingelheim, Covidien and Pfizer. JMO has received honoraria from Astra Zeneca, Boehringer Ingelheim , Bristol Myers Squibb, Pfizer and Servier. PS declares that he was Chief Investigator of the IST-3 trial, funded by the Medical Research Council, the Stroke Association and the Health Foundation, the IST -3 pilot study was supported by a donation of drug and placebo from Boehringer Ingelheim, and PS has received Honoraria and Travel expenses paid to his Department from Boehringer Ingelheim. DT reports honoraria from Boehringer Ingelheim, Bayer and Pfizer. KT has received research grant support from the Japan Agency for Medical Research and Development, and fees from Mitsubishi Tanabe Pharma. JW declares trial funding from the Medical Research Council, Efficacy and Mechanism Evaluation Programme, Stroke Association and Health Foundation. WNW was funded by a Medical Research Council Clinician Scientist Fellowship (G0902303). WH reports honoraria from Boehringer Ingelheim, Daiichi Sankyo and Bayer, receipt of an unrestricted research grant from Boehringer Ingelheim to perform the ECASS 4 EXTEND trial, and past chairmanship of the ECASS 1-3 thrombolysis trials. WH is current president of the World Stroke Organisation. GH, MKo, ML and GM declare no conflict of interest. Figure legends Figure 1: Effect of rt−PA on an excellent stroke outcome (mRS0−1) in groups defined by the current EU label as well as an EU label without an upper age restriction For each of panels a, b and c, the odds ratios represented by open diamonds or open squares are derived from trial−stratified logistic regression estimates adjusted only for treatment allocation. By contrast, the odds ratios represented by filled squares are derived from trial-stratified logistic regression models which allow separate estimation of the OR at different levels of, respectively, treatment delay, age and baseline NIHSS, with further adjustment for the other two baseline characteristics (but not for possible interactions with those characteristics). Consequently, the information-weighted average of the subgroup-specific estimates does not necessarily equal the summary odds ratios shown by the open diamonds (main effect estimates which are additionally adjusted for baseline treatment delay, age and baseline NIHSS are shown in Webtable 4). Figure 2: Effect of rt-PA on 90-day mortality in groups defined by the current and extended labels in the EU and US For both the EU and US label, and each of the panels a, b and c, Cox proportional hazards regression with stratification by trial and adjustment only for treatment allocation was used to estimate the hazard ratio and its 95% confidence interval for each period at risk. Patients can only contribute to a particular risk period if they have already survived any preceding periods. Denominators therefore reflect the numbers of patients at risk of death at the start of each shown period. Figure 3: Effect of rt−PA on an excellent stroke outcome (mRS0−1) in groups defined by the current US label as well as a US label with a 4.5h time window For each of panels a, b and c, the odds ratios represented by open diamonds or open squares are derived from trial−stratified logistic regression estimates adjusted only for treatment allocation. By contrast, the odds ratios represented by filled squares are derived from trial-stratified logistic regression models which allow separate estimation of the OR at different levels of, respectively, treatment delay, age and baseline NIHSS, with further adjustment for the other two baseline characteristics (but not for possible interactions with those characteristics). Consequently, the information-weighted average of the subgroup-specific estimates does not necessarily equal the summary odds ratios shown by the open diamonds (main effect estimates which are additionally adjusted for baseline treatment delay, age and baseline NIHSS are shown in Webtable 4). Figure 4: Distribution of mRS at 3−6 months by randomized treatment allocation in groups defined by the current and extended labels in the EU and US mRS score was ascertained at 6 months for IST−3 and 3 months for other trials. References 1. Actilyse Specimen of Product Characteristics. [18th January 2017]; Available from: https://www.medicines.org.uk/emc/medicine/308. 2. ACTIVASE Highlights of Prescribing Information, Revised 02/2015. [18th January 2017]; Available from: http://www.gene.com/download/pdf/activase_prescribing.pdf. 3. Karolinska Stroke Update. Consensus Statements 2012: Update on intravenous thrombolysis. [18th January 2017]; Available from: http://www.strokeupdate.org/Cons_Reperf_IVT_2012.aspx. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, Demchuk AM, Fugate JE, Grotta JC, et al. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke; a journal of cerebral circulation. 2016;47(2):581-641. Epub 2015/12/24. 5. Minematsu K, Toyoda K, Hirano T, Kimura K, Kondo R, Mori E, et al. Guidelines for the Intravenous Application of Recombinant Tissue-type Plasminogen Activator (Alteplase), the Second Edition, October 2012: A Guideline From the Japan Stroke Society. J Stroke Cerebrovasc. 2013;22(5):571-600. 6. Anani N, Mazya MV, Bill O, Chen R, Koch S, Ahmed N, et al. Changes in European Label and Guideline Adherence After Updated Recommendations for Stroke Thrombolysis Results From the Safe Implementation of Treatments in Stroke Registry. Circ-Cardiovasc Qual. 2015;8(6):S155-S62. 7. Gumbinger C, Reuter B, Hacke W, Sauer T, Bruder I, Diehm C, et al. Restriction of therapy mainly explains lower thrombolysis rates in reduced stroke service levels. Neurology. 2016;86(21):1975-83. 8. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;doi:10.1016/S0140-6736(14)60584-5. Epub 2014/08/12. 9. Lees KR, Emberson J, Blackwell L, Bluhmki E, Davis SM, Donnan GA, et al. Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials. Stroke; a journal of cerebral circulation. 2016;47(9):2373-9. Epub 2016/08/11. 10. Whiteley WN, Emberson J, Lees KR, Blackwell L, Albers G, Bluhmki E, et al. Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis. Lancet neurology. 2016;15(9):925-33. Epub 2016/06/13. 11. Berge E, Cohen G, Roaldsen MB, Lundstrom E, Isaksson E, Rudberg AS, et al. Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial. Lancet neurology. 2016;15(10):1028-34. 12. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. The New England journal of medicine. 1995;333(24):1581-7. Epub 1995/12/14. 13. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA : the journal of the American Medical Association. 1995;274(13):1017-25. Epub 1995/10/04. 14. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352(9136):1245-51. Epub 1998/10/27. 15. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England journal of medicine. 2008;359(13):1317-29. Epub 2008/09/26. 16. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA : the journal of the American Medical Association. 1999;282(21):2019-26. Epub 1999/12/11. 17. Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet neurology. 2008;7(4):299-309. Epub 2008/02/26. 18. Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352-63. Epub 2012/05/29. 19. The Stroke Thrombolysis Trialists’ Collaborative Group. Details of a prospective protocol for a collaborative meta-analysis of individual participant data from all randomized trials of intravenous rt-PA vs. control: statistical analysis plan for the Stroke Thrombolysis Trialists' Collaborative meta-analysis. Int J Stroke. 2013;8(4):278-83. 20. Rahlfs VW, Zimmermann H, Lees KR. Effect Size Measures and Their Relationships in Stroke Studies. Stroke; a journal of cerebral circulation. 2014;45(2):627-33. 21. Mccullagh P. Regression-Models for Ordinal Data. J Roy Stat Soc B Met. 1980;42(2):109-42. 22. Cameron A, Bogie J, Abdul-Rahim A, Ahmed N, Mazya M, Mikulik R, et al. Professional guideline versus product license selection for treatment with IV thrombolysis: compliance with produce licenses is highest in lower efficiency sites and restricts thrombolysis usage. Eur Stroke J. 2017 (in press). Table 1: Contraindications to alteplase treatment for stroke in FDA and EMA approved product inserts and AHA and ESO guidelines
*states “the risks of bleeding are increased and should be weighed against the benefits”, not contraindication Not including exclusion of recent bleeding, ICrH on scan, GI bleeding, trauma (<3 months), recent severe bleeding. Surgery, hepatic disease, cirrhosis, hepatitis, cancers with increased bleeding risk, GI-ulcer, varices, non-compressible site puncture, heart massage, recent delivery, pancreatitis are only mentioned in the EMA insert. References FDA: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103172s5203lbl.pdf EMA: https://www.medicines.org.uk/emc/medicine/308#STORAGE China: http://onlinelibrary.wiley.com/doi/10.1111/cns.12126/full AHA: http://stroke.ahajournals.org/content/44/3/870 ESO: http://www.congrex-switzerland.com/fileadmin/files/2013/eso-stroke/pdf/ESO08_Guidelines_Original_english.pdf, update http://www.congrex-switzerland.com/fileadmin/files/2013/eso-stroke/pdf/ESO_Guideline_Update_Jan_2009.pdf Table 2: Baseline characteristics of participants involved in the 8 trials that tested alteplase 0.9 mg/kg versus control, subdivided according to whether the participant met all of the criteria in the current EU or US labels
Categorical data presented as n (column %), continuous data presented as mean (SD). * Participants can fail to meet the current label for any of several possible reasons (listed in Table 3). For example, of the 1568 participants who failed to meet the current EU label despite receiving treatment within 4.5 hours, 1270 (81%) failed because they were aged >80 years and the remaining 298 (19%) failed for other reasons, while of the 288 patients who failed to meet the current US label despite receiving treatment within 3 hours, all either had SBP >175 or DBP>110 mmHg. Directory: portal -> files files -> Is it possible to construct a canon of tv programmes? Immanent reading versus textual-historicism files -> Lawrence Peter Ampofo files -> Impact case study (ref3b) files -> Ethics and Factual Television: a short history files -> P. O. Box 27, 00014 University of Helsinki, Finland tel. 358-9-191 58080 / 22216; fax 358-9-191 58096 / 23008 files -> The impact of a pledge campaign and the promise of publicity: a randomized controlled trial of charitable donations files -> Diversity and Voice: the Political Participation of Young People in the European Union Download 183.41 Kb. Share with your friends:
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